Compromised cerebral perfusion, also known as brain ischemia after various cerebral insults such as cerebrovascular accidents (CVA) including ischemic or hemorrhagic stroke, subarachnoid hemorrhage, subdural hemorrhage, intracerebral hemorrhage or chronic conditions, and traumatic brain injury (TBI) invariably leads to neuronal death in a restricted area or “core” due to lack of oxygen and nutrient delivery. The brain is especially vulnerable to oxygen and nutrient deprivation because of its high rate of metabolism consuming 25% of whole body oxygen uptake while representing only approximately 3-4% of total body weight while lacking significant oxygen or glucose stores. Brain tissue oxygen is depleted within 6 seconds and the EEG is isoelectric with 25 seconds of complete circulatory arrest. Brain ischemia can be acute as in acute ischemic stroke or chronic (i.e., long-lasting) as in vascular dementia. Acute ischemia is a neurologic emergency because irreversible damage to tissues can occur within several minutes whereas chronic ischemia may occur in slow developing ischemic diseases as in vascular dementia, Alzheimer's Disease or in sickle cell disease.
Stroke and traumatic brain injury are the most frequent cerebral insults complicated by acute ischemia, and are serious global health problems causing long-term disability. Each year, about 800,000 people suffer new or recurrent stroke, which kills 130,000 of them and causes loss to the United States economy of $71.55 billion [1, 2]. Annually, 1.7 million people suffer TBI, 52,000 die and 275,000 are hospitalized for long periods of time due to secondary injury complications [3, 4]. The annual economic burden for TBI in the United States is approximately $60 billion. More than 1.1 million Americans are living with permanent functional disabilities resulting from stroke and 5.3 million from TBI representing more than 2% of the US population. Currently, there are no neuroprotective strategies proven effective in improving outcome after CVA or TBI despite the many therapies that have been found effective in animals only to fail in clinical trials. In the treatment of acute ischemic stroke, thrombolysis with tissue plasminogen activator (tPA) for thrombolysis of the clot is the only FDA approved treatment. However, only 5-7% of patients qualify for thrombolytic therapy due to the increased with time after stroke risk of hemorrhagic transformation [5, 6] and only about 30% of those treated recanalize. Notably, none of the neuroprotective therapies tested thus far have sought to focus on hemorheological restoration or improvement of impaired microvascular perfusion.
Traumatic brain injury (TBI) with post-traumatic high intracranial pressure (ICP) [3,4], another condition leading to brain ischemia, also known as intracranial hypertension, is fatal by arresting cerebral blood flow (CBF) to the entire brain even in cases of focal injury. It leads to cerebral edema and expansion of the blood volume within the brain, tissue compression, shift in brain structures, and brain herniation restricting blood supply to the entire brain leading to brain death.
Other incidents and conditions associated with acute or chronic brain ischemia are: global cerebral ischemia caused by cardiac arrest, heart failure or hemorrhagic shock; chronic intracranial hypertension, including idiopathic intracranial hypertension, hydrocephalus and pseudo tumor cerebri; mild cognitive impairment, including vascular dementia and Alzheimer's disease; systemic lupus erythromatosus; multiple sclerosis; Moyamoya disease; transient ischemic attacks; hypertensive encephalopathy and ruptured aneurysm.
The treatments available for ischemia are limited and require novel solutions which involve looking at the problem and possible solutions from a new perspective. Numerous neuroprotective treatments found effective in animals, have failed to translate clinically [7, 8].
As a specific example, Alzheimer's disease (AD) which presently affects more than 5 million Americans and projected to increase to 16 million by 2050 [1], is a consequence of complex interactions of age-related neurodegeneration and vascular-associated pathologies. The quantitative neuropathologic criteria for AD diagnostics as well as the main target for treatment options are the degree of deposition of amyloid plaques and Tau protein neurofibrillary tangles [2]. However, treatments aimed to prevent or remove amyloid plaques have not succeeded in preventing or reducing dementia [3, 4].
Similarly, to date, the only FDA-approved treatment for ischemic stroke, tissue plasminogen activator (tPA), is used only in 5% of these patients because the therapeutic window is prohibitively short (3 hours after the event) due to a 10-fold increased incidence of intracranial hemorrhage with 50% mortality [5, 6]. In recent years, studies showed the importance of collateral flow which may provide an alternative route for blood to reach the ischemic tissue and partially maintain oxygen support in ischemic stroke [29]. Extensive anastomotic connections between the anterior and middle cerebral arteries have been shown after occlusion [30, 31] and persisted for 24 hours [30]. It is suggested that enhancement of collateral blood flow to ischemic territories may benefit stroke patients. Studies showed that collateral treatment such as i.v. injection of high dose of albumin blood pressure augmentation [32] and partial occlusion of the aorta [33, 34] may reduce infarction and improve recovery after stroke, however, these methods have various complications [35], like volume expansion, hemodilution and reduced viscosity which improved microvascular perfusion in rodents but worsened outcome in patients due to pulmonary edema (albumin).
Therefore, new, effective approaches to treat, ameliorate or prevent brain ischemia caused by various etiologies are still urgently needed.